The present application relates to angiogenesis, and more particularly to the electrically mediated upregulation of angiogenic factors to promote revascularization of ischemic body tissue.
Current medical practices call for diagnosing, testing and treating certain maladies and injuries with various agents. In the past few years there have been great strides in the development of agents that have improved therapeutic and diagnostic application. For example, scientists and medical researchers are rapidly developing genetic materials and other agents that cause cells to participate in the generation of new blood vessels; a process called angiogenesis. There are believed to be two main types of vascular disease which are especially suitable for treatment by angiogenesis therapy, namely coronary artery disease and peripheral vascular disease.
Coronary artery disease is a disease that restricts the flow of blood to the myocardial tissue of the heart. This restricted blood flow is commonly caused by a blockage or blockages resulting from a disease process known as arteriosclerosis. The blockages can cause an infarction where the flow of blood to a certain part of the myocardium or cardiac muscle is interrupted, generally resulting in a localized area of dead myocardial tissue that is surrounded by an area of myocardial tissue receiving reduced blood flow. This area of reduced blood flow is called a zone of ischemia. Other people suffer from diffuse coronary disease, which is the blockage of many coronary arteries. By-passing or reopening all of these arteries is not an option because of the extreme procedural difficulties and trauma that such a procedure would cause. As a result, there exists a need to provide an adequate flow of blood to ischemic areas of the heart without resorting to by-pass surgery or efforts to reopen the blocked vessels. Ischemia in the heart is generally present in those with coronary vessel blockage which results in a heart attack.
Peripheral vascular disease is indicated when blood flow is restricted to areas other than the myocardium. These ischemic areas are often induced by vascular blood clots or degenerative diseases. One example is the ischemic limb. The ischemic limb often occurs in patients having diseases such as diabetes. In a diabetic patient, the small vessels are often destroyed causing certain tissue areas to be oxygen and nutrient deficient, or ischemic. Areas of ischemic tissue also result from strokes. In the case of a stroke, the cerebral blood flow is impaired due to a thrombosis, hemorrhage or embolism.
One way to address the need for improved blood flow to ischemic tissues in the body is to treat such tissues in such a way that the tissue or tissues generate new blood vessels. As stated above, the process of creating or generating new blood vessels is called angiogenesis. One method to promote angiogenesis is by direct injection of an angiogenic agent. One technique for delivery of such an agent to an ischemic area involves the direct injection of genetic material in or near the ischemic area to promote angiogenesis.
In practice, however, direct injection also has many shortcomings. One shortcoming is the inefficiency in transferring the genetic material into the cells and relatively low level of stable transfection of the genetic material within target cells. The transfection efficiency of such local such delivery by direct injection is generally believed to be about 1% to 2%.
Another method of direct injection employs electroporation, or a treatment of tissue with a series of high-energy electrical pulses to porate the tissue and allow the genetic material to enter. One problem with this approach is that many healthy cells are frequently killed in the process and overall transfection is still not very high.
The inability to effectively deliver the angiogenic agent to the targeted area, therefore is one of the major limitations of the use of such agents. During delivery of such agents, large amounts are often destroyed or lost to general circulation. This is inefficient, expensive, and can promote toxicity in certain regions. Other side effects are also possible in healthy tissue due to the inefficiency of such local delivery methods.
Therefore, there is a need for improved methods for enhancing angiogenesis and the cellular expression of agents to promote angiogenesis. There is also a need for a treatment apparatus that is cost effective and reduces the risk of side effects. There is also a need for a method and/or device that utilizes the body""s natural healing mechanisms to promote angiogenesis, while avoiding the need for any introduction of foreign agents.
The present invention provides an electrical stimulation apparatus for delivering an electrical field to a targeted body tissue over a predetermined period of time in order to stimulate a cell-initiated angiogenic response in living cells within the targeted body tissue. The electrical stimulation apparatus having an electrical field generating unit including a power supply and a control mechanism interconnected with the power supply; and a plurality of electrodes designed to deliver an electrical field to the targeted body tissue. The plurality of electrodes are in electrical communication with the power supply and the control mechanism controls an amplitude and a duration of a period of delivery of electrical pulse from the power supply to the respective electrodes and through the targeted body tissue when the electrodes are in contact with the targeted body tissue at a plurality of first locations. The amplitude of the electrical field delivered to the targeted body tissue and the duration of the period of delivery is sufficient to stimulate angiogenesis in the targeted body tissue; preferably by causing living cells within the targeted body tissue to increase vascular endothelial growth factor (VEGF) expression.
In one embodiment of the present invention, the electrical field generating unit is a constant current delivery device and the electrical field is generated by the constant current delivery device. The amplitude of the electrical current delivered to the targeted body tissue by the constant current delivery device is preferably from about 01. mA to about 250 mA and the duration of the period of delivery is preferably equal to or greater than about 1 ms.
In another embodiment of the present invention, the electrical field generating unit is a constant voltage delivery device and the electrical field is generated by the constant voltage delivery device. The amplitude of the electrical voltage delivered to the targeted body tissue by the constant voltage delivery device is preferably a generally constant voltage of from about 50V/cm to about 300V/cm. In further preferred embodiments, the electrical field is produced by a number of pulses in the range of from 1 to about 1000 pulses with a frequency between about 0. 1 Hz to about 5 Hz and the electrical field is preferably generated for a duration between about 0.0001 seconds to several days.
In other preferred embodiments, the control mechanism includes a computer processing unit in electronic communication with the power supply, the computer processing unit being programmed to cause the electrical stimulation apparatus to deliver a predetermined amount of electrical current or voltage over a predetermined period of delivery to the plurality of electrodes such that the electrical stimulation apparatus can deliver such electrical current or voltage to the targeted body tissue when the plurality of electrodes are in contact or in proximity with the targeted body tissue. In other preferred embodiments, the plurality of electrodes are configured in a manner selected from the group consisting of unipolar, bipolar, and multiple electrode configurations and the apparatus is preferably designed and configured to be implantable.
The present invention also includes a method of treatment of targeted body tissues by: (1) providing living cells, preferably autologous or heterologous living cells, more preferably autologous or heterologous myocardial cells for treatment of myocardial tissue, which, in the case of autologous cells, have been removed from the prospective patient, which are biologically compatible with the targeted body tissue; (2) stimulating the living cells with an electrical field sufficient in a manner describe herein to increase VEGF expression by the living cells, wherein the amplitude of the electrical field delivered to the targeted body tissue and the duration of the period of delivery is sufficient to cause the living to increase VEGF expression; and (3) injecting the stimulated cells into the targeted body tissue.
The present invention has several advantages. For example, angiogenesis can be promoted without the delivery of foreign agents, which allows the body to heal naturally and minimizes potential for side effects. The procedure provides minimum discomfort and may be performed on an outpatient basis. The main power supply can be reused, while the electrodes are disposable. A combination of a reusable power supply and disposable sterilized electrodes reduces both the expense and the chance of contamination. Yet another advantage is that electrical energy can be applied for extended periods of time with minimal risk of killing the target cells.
Another advantage is that the present invention can be used to treat deep tissues, as well as superficial tissue. Certain techniques may be either invasive, minimally invasive, or noninvasive. Furthermore, the treatment of the ischemic tissue can be targeted while exposure to healthy tissue is minimized.
The above described features and advantages along with various other advantages and features of novelty are pointed out with various other advantages and features of novelty are pointed out with particularity in the claims of the present application. However, for a better understanding of the invention, its advantages, and objects attained by its use, reference should be made to the drawings which form a further part hereof and to the accompanying descriptive matter in which there is illustrated and described preferred embodiments of the invention.